1. The Field of the Invention
The present invention relates to stable pharmaceutical solution formulations to be used with pressurized metered dose inhalers (MDIs) suitable for aerosol administration. In particular, the present invention relates to solutions to be used with pressurized metered dose inhalers (MDIs), which are suitable for aerosol administration containing an active ingredient highly susceptible to chemical degradation selected from a group consisting of 20-ketosteroids and quinolinone derivatives, which is stabilized by the presence of a sequestering agent.
2. The Relevant Technology
Pressurized metered dose inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.
Drugs commonly delivered by inhalation include bronchodilators such as β2-agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic efficacy and reducing side effects.
MDIs use a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol.
Since the halogenated propellants such as chlorofluorocarbons, commonly called Freons or CFCs, have been banned as known to deplete the ozone layer, HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems have been disclosed.
Formulations for aerosol administration via MDIs can be solutions or suspensions. Solution formulations offer the advantage of being homogeneous with the active ingredient and excipients completely dissolved in the propellant vehicle or its mixture with suitable co-solvents such as ethanol. Solution formulations also obviate physical stability problems associated with suspension formulations so assuring more consistent uniform dosage administration.
Recently many types of active ingredients have been reformulated as solutions in non CFC hydrofluorocarbon (HFC) propellants with ethanol.
However, it has been noticed in this kind of formulations that due to the higher polarity of the HFA propellants, in particular of HFA 134a having a dielectric constant of D≧9.5, with respect to CFC vehicles of D≦2.3, the active ingredient may suffer of chemical stability problems and degrade during storage. Chemical degradation is especially problematic when the compound is dissolved in the formulation.
Chemical degradation of the active ingredient may occur by various mechanisms, the most significant being the oxidative degradation by molecular oxygen, catalysed by the presence of heavy metal ions, such as aluminium, ferric or cupric ions, and the hydrolysis or esterification phenomena which are pH dependent.
Consequently, attempts to increase the stability of the active ingredients have been directed to lower the pH and minimize the amount of heavy metal ions in the aerosol formulation.
As to the pH lowering, WO 94/13262 suggests using acids as stabilizers for reducing the interaction of the ative ingredient with the cosolvent and/or water present in the solution formulation. Most examples related to ipratropium bromide, an anticholinergic drug and an example was presented for a β2-agonist, i.e., fenoterol. No difference is made in the application between the use of organic and inorganic acids and organic acids are preferably used. In WO 01/89480 of the applicant, stability data of a HFA 134a solution formulation containing 32 adrenergic agonists and in particular formoterol and 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride (TA 2005) stabilized by different amounts of HCl 1.0M or 0.08M were reported. Phosphoric acid is mentioned but not exemplified.
In WO 2003/087097 propellant-free inhalable solutions or suspensions containing a combination of β2-agonists and anticholinergics have been described. Both organic and inorganic acids were used to adjust the pH. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. According to this document, it is particularly preferred to use hydrochloric acid to adjust the pH. Analogous formulations have been described in WO 2004/004704 referred to propellant-free inhalable solutions or suspensions containing a combination of anticholinergics and PDE-IV inhibitors.
As to the minimization of heavy metal ions, WO 00/78286 ('286) and WO 00/30608 ('608), propose the use of aerosol containers with inert interior surfaces.
WO 96/40042 disclosed that aqueous formulations of triamcinolone acetonide in neutral or basic solutions undergo oxidative degradation catalyzed by trace levels of metal ions, especially copper, and proposes the use of EDTA as sequestering agent and/or adjusting pH. The rate of disappearance of triamcinolone acetonide in aqueous solution exhibited a dependency on the buffer concentration at constant pH and ionic strength. EDTA even in a very low concentration had a profound inhibitory effect of the degradation.
Solution formulations of flunisolide in HFC/HFA propellants were disclosed in WO 95/17195, where it is indicated that chemical stability may be enhanced by using additives like water, sorbitan trioleate, and cetylpyridinium chloride, and also that certain containers such as glass and resin coated aluminum enhance chemical stability and/or minimize the absorption of flunisolide onto the container wall.